Accumulation of Pro-Cancer Cytokines in the Plasma Fraction of Stored Packed Red Cells
Douglas Benson*1,2, ADAM W. Beck3, Marie Schluterman3, Rolf a. Brekken3, Christopher Silliman1,4, Carlton C. Barnett1,2
1Surgery, University of Colorado at Denver HSC, Aurora, CO; 2Surgery, Denver Health Medical Center, Denver, CO; 3Surgery, University of Texas at Southwestern Medical Center, Dallas, TX; 4Bonfils Blood Center, Denver, CO
Introduction
Perioperative blood transfusion has been linked to decreased survival in cancer; however the exact causal mechanism has not been elucidated. Allogeneic transfusions are known to expose patients to foreign cells and lipid mediators. We hypothesize stored packed red cells contain pro-cancer cytokines that augment tumor progression.
Methods
Chemiarray analysis for pro-cancer cytokines was performed on the acellular fraction of stored leukocyte reduced (LR) and non leukocyte reduced (NLR) packed red blood cells (pRBCs) at days 1(D1) and 42 (D42 -outdate) of storage. This analysis revealed elevated levels of angiogenin, EGF, MCP-1, PDGF, RANTES, and TNF-α. Specific enzyme-linked immunosorbent assay was performed for each of these cytokines to confirm elevation. Blood products from each donor were compared to evaluate differences in storage time and leukoreduction on cytokine concentration. Data were analyzed by ANOVA; p≤0.05 significant; N≥4 per group.
Results
Angiogenin levels were different between LR and NLR blood, 0ng/ml (undetectable) vs. 44.2±3.7ng/ml (p<0.001) at D1. Storage time had no effect on concentration. EGF levels are similar at D1 in LR v NLR, 216.4±3.8pg/ml vs. 241.1±13.1pg/ml, and increased with storage time in NLR blood only, 1436.4±238.6pg/ml at D42 (p=0.001). MCP-1 levels were increased with storage time in LR, 86.3±6.3pg/ml at D1 vs. 121.2±6.1pg/ml at D42 (p=0.007), and increased markedly in NLR, 78.2±7.3pg/ml at D1 vs. 647.8±220.7pg/ml at D42 (p=0.02). PDGF levels are reduced in LR compared to NLR, 6.8±0.2ng/ml vs. 61.6±6.0ng/ml (p<0.001), and increased with storage time only in NLR, 34.7±9.7ng/ml at D1 vs. 76.5±1.7ng/ml by D42 (p=0.003). RANTES levels are reduced in LR compared to NLR, 7.2±1.6ng/ml vs. 14.2±0.8ng/ml (p<0.001), with no changes with storage time. TNF alpha levels were not different between LR and NLR with no storage time effect between D1 and D42.
Conclusion
Multiple factors were identified in pRBCs that can augment tumor progression. These data reveal a trend toward elevated pro-cancer cytokines in non leukocyte reduced pRBCs and significant accumulation during storage. The negative affects of blood transfusion are likely multi-factorial, and the cytokines identified herein may represent possible therapeutic targets to offset negative effects of transfusion. Further, routine leukocyte reduction may diminish untoward affects of pRBCs transfusion.
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